Journal articles on the topic 'Delayed Death Inhibitors'
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Amberg-Johnson, Katherine, and Ellen Yeh. "Host Cell Metabolism Contributes to Delayed-Death Kinetics of Apicoplast Inhibitors inToxoplasma gondii." Antimicrobial Agents and Chemotherapy 63, no. 2 (November 19, 2018): e01646-18. http://dx.doi.org/10.1128/aac.01646-18.
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ABSTRACTToxoplasma gondiiand related human parasites contain an essential plastid organelle called the apicoplast. Clinically used antibiotics and other inhibitors that disrupt apicoplast biogenesis cause a mysterious “delayed-death” phenotype in which parasite growth is unaffected during the first lytic cycle of inhibitor treatment but is severely inhibited in the second lytic cycle even after drug removal. Critical to understanding the complex downstream cellular effects of these drug classes are the timing of apicoplast loss during inhibitor treatment and how it relates to this peculiar growth phenotype. Here we show that, upon treatment with diverse classes of apicoplast inhibitors, newly replicatedT. gondiiparasites in the first lytic cycle initially form apicoplasts with defects in protein import or genome replication and eventually fail to inherit the apicoplast altogether. Despite the accumulation of parasites with defective or missing apicoplasts, growth is unaffected during the first lytic cycle, as previously observed. Strikingly, concomitant inhibition of host cell isoprenoid biosynthesis results in growth inhibition in the first lytic cycle and unmasks the apicoplast defects. These results suggest that defects in and even the complete loss of the apicoplast inT. gondiiare partially rescued by scavenging of host cell metabolites, leading to death that is delayed. Our findings uncover host cell interactions that can alleviate apicoplast inhibition and highlight key differences in delayed-death inhibitors betweenT. gondiiandPlasmodium falciparum.
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Ramya, T. N. C., Satyendra Mishra, Krishanpal Karmodiya, Namita Surolia, and Avadhesha Surolia. "Inhibitors of Nonhousekeeping Functions of the Apicoplast Defy Delayed Death in Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 51, no. 1 (October 23, 2006): 307–16. http://dx.doi.org/10.1128/aac.00808-06.
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ABSTRACT Targeting of apicoplast replication and protein synthesis in the apicomplexan Toxoplasma gondii has conventionally been associated with the typical “delayed death” phenotype, characterized by the death of parasites only in the generation following drug intervention. We demonstrate that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number. Interestingly, however, molecules like triclosan, cerulenin, fops, and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, an inhibitor of heme biosynthesis that operates in the apicoplast of the parasite, display rapid and striking parasiticidal effects. Our results draw a clear distinction between apicoplast functions per se and the apicoplast as the site of metabolic pathways, which are required for parasite survival, and thus subserve the development of novel antimalarial therapy.
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Kindy, Mark S. "Inhibition of Tyrosine Phosphorylation Prevents Delayed Neuronal Death following Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 13, no. 3 (May 1993): 372–77. http://dx.doi.org/10.1038/jcbfm.1993.50.
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Protein tyrosine phosphorylation plays an important role in the regulation of neuronal function. We examined the effects of inhibition of tyrosine phosphorylation on ischemic neuronal damage in the CA1 region of the hippocampus. In the gerbil hippocampus, genistein and lavendustin A, tyrosine kinase inhibitors, were administered 30 min before initiation of 5-min ischemia and reperfusion. Both genistein and lavendustin A blocked tyrosine phosphorylation and prevented delayed neuronal death (DND). However, genistin, an inactive analogue of genistein, did not block DND. Genistein was dose-dependent in the inhibition of DND after ischemia and reperfusion. Administration of genistein 5 to 10 min after ischemia and reperfusion was ineffective in blocking DND in the CA1 region of the hippocampus. The tyrosine kinase inhibitors selectively blocked the phosphorylation of microtubule-associated protein (MAP)-2 kinase following ischemia and reperfusion injury. These results suggest that tyrosine phosphorylation in the ischemic brain is important for neuronal injury and that MAP-2 kinase may play a role in the onset of delayed neuronal death.
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Weil, M., M. D. Jacobson, and M. C. Raff. "Are caspases involved in the death of cells with a transcriptionally inactive nucleus? Sperm and chicken erythrocytes." Journal of Cell Science 111, no. 18 (September 15, 1998): 2707–15. http://dx.doi.org/10.1242/jcs.111.18.2707.
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We show that mouse sperm die spontaneously within 1–2 days in culture and that treatment with either staurosporine (STS) and cycloheximide (CHX) or a peptide caspase inhibitor does not accelerate or delay the cell death. Chicken erythrocytes, by contrast, are induced to die by either serum deprivation or treatment with STS and CHX, and embryonic erythrocytes are more sensitive than adult erythrocytes to both treatments. Although these erythrocyte deaths display a number of features that are characteristic of apoptosis, they are not blocked, or even delayed, by peptide caspase inhibitors, and most of the cells die without apparently activating caspases. A small proportion of the dying erythrocytes do activate caspase-3, but even these cells, which seem to be the least mature erythrocytes, die just as quickly in the presence of caspase inhibitors. Our findings raise the possibility that both mouse sperm and chicken erythrocytes have a death programme that may not depend on caspases and that chicken erythrocytes lose caspases as they mature. Chicken erythrocytes may provide a useful ‘stripped down’ cell system to try to identify the protein components of such a death programme, which may serve to back-up the conventional caspase-dependent suicide mechanism in many cell types.
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Shishido, Yoshiyuki, Masayoshi Furushiro, Shuichi Tanabe, Shigenobu Shibata, Shusuke Hashimoto, and Teruo Yokokura. "Effects of prolyl endopeptidase inhibitors and neuropeptides on delayed neuronal death in rats." European Journal of Pharmacology 372, no. 2 (May 1999): 135–42. http://dx.doi.org/10.1016/s0014-2999(99)00185-5.
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Jäckle, Tina, Cornelia Hasel, Ingo Melzner, S. Brüderlein, Peter M. Jehle, and Peter Möller. "Sustained hyposmotic stress induces cell death: apoptosis by defeat." American Journal of Physiology-Cell Physiology 281, no. 5 (November 1, 2001): C1716—C1726. http://dx.doi.org/10.1152/ajpcell.2001.281.5.c1716.
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We describe sustained hyposmotic stress as a novel type of environmental condition enforcing apoptosis. In a dose- and time-dependent fashion, hyposmotic stress leads to a delayed type of apoptosis with considerable variations in constitutive sensitivity among different cell types. For example, after 48 h at 84 mosmol/l, the death rate ranged from 10.8 ± 0.7% in AsPc1 human pancreatic carcinoma cells to 72.0 ± 1.6% in HK-2 human kidney tubule cells. Caspase inhibitors rendered cells more resistant to hyposmolar stress; the caspase 3 inhibitor Ac-Asp-Glu-Val-aspartic acid aldehyde was the most efficient. After 24 h of stress, HT-29 colon carcinoma and HK-2 cells had increased their mitochondrial mass. This went along with an increase in mitochondrial membrane potential in HT-29 cells but with a decrease in HK-2 cells. Starting at 2 h of stress, we detected transient CD95L transcription followed by surface expression of CD95L in HT-29 but not in HK-2 cells. Inhibitory CD95L antibody partially inhibited specific death in HT-29 but not in HK-2 cells. Thus, as in other types of stress-induced apoptosis, the CD95/CD95L system is one of the different routes to suicide optionally used by hyposmotically stressed cells. Our findings may have clinical implications for the prevention and treatment of tissue damage caused by severe hyposmolar states.
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Nakagomi, T., T. Sasaki, T. Kirino, A. Tamura, M. Noguchi, I. Saito, and K. Takakura. "Effect of cyclooxygenase and lipoxygenase inhibitors on delayed neuronal death in the gerbil hippocampus." Stroke 20, no. 7 (July 1989): 925–29. http://dx.doi.org/10.1161/01.str.20.7.925.
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Lewin, Matthew, José Gutiérrez, Stephen Samuel, María Herrera, Wendy Bryan-Quirós, Bruno Lomonte, Philip Bickler, Tommaso Bulfone, and David Williams. "Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom." Toxins 10, no. 10 (September 20, 2018): 380. http://dx.doi.org/10.3390/toxins10100380.
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There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A2 (sPLA2) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA2 inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts.
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Duval, R., V. Bellet, S. Delebassée, and C. Bosgiraud. "Implication of caspases during maedi–visna virus-induced apoptosis." Journal of General Virology 83, no. 12 (December 1, 2002): 3153–61. http://dx.doi.org/10.1099/0022-1317-83-12-3153.
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Maedi–visna virus (MVV) causes encephalitis, pneumonia and arthritis in sheep. In vitro, MVV infection and replication lead to strong cytopathic effects characterized by syncytia formation and subsequent cellular lysis. It was demonstrated previously that MVV infection in vitro induces cell death of sheep choroid plexus cells (SCPC) by a mechanism that can be associated with apoptotic cell death. Here, the relative implication of several caspases during acute infection with MVV is investigated by employing diverse in vitro and in situ strategies. It was demonstrated using specific pairs of caspase substrates and inhibitors that, during in vitro infection of SCPC by MVV, the two major pathways of caspase activation (i.e. intrinsic and extrinsic pathways) were stimulated: significant caspase-9 and -8 activities, as well as caspase-3 activity, were detected. To study the role of caspases during MVV infection in vitro, specific, cell-permeable, caspase inhibitors were used. First, these results showed that both z-DEVD-FMK (a potent inhibitor of caspase-3-like activities) and z-VAD-FMK (a broad spectrum caspase inhibitor) inhibit caspase-9, -8 and -3 activities. Second, both irreversible caspase inhibitors, z-DEVD-FMK and z-VAD-FMK, delayed MVV-induced cellular lysis as well as virus growth. Third, during SCPC in vitro infection by MVV, cells were positively stained with FITC-VAD-FMK, a probe that specifically stains cells containing active caspases. In conclusion, these data suggest that MVV infection in vitro induces SCPC cell death by a mechanism that is strongly dependent on active caspases.
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Schweber, Sarah J., Alicia G. Rodriguez-LaRocca, Valerie Calvert, Emanuel Petricoin, Susan Band Horwitz, Eleni Andreopoulou, and Hayley M. McDaid. "Protein pathway activation mapping guided biomarker development to identify optimal combinations of MEK inhibitor with PI3K/mTOR pathway inhibitors for the treatment of triple-negative breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2612. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2612.
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2612 Background: Activated MAPK and PI3K pathway signaling are associated with poor prognosis in triple negative breast cancer (TNBC). Although some TNBC cell models are sensitive to MEK inhibition, feedback activation of the PI3K pathway mediates resistance. Thus, suppression of both arms of the MAPK/PI3K/mTOR network is a rational approach to targeting TNBC. Here we explore the anti-tumor efficacy of combinations of MEK inhibitor with PI3K, AKT, or mTOR inhibitors with a focus on biomarker development. Methods: Combinations of the MEK inhibitor PD-0325901 with the PI3K inhibitor GDC-0941, AKT inhibitor MK-2206, dual mTORC 1/2 inhibitor Torin 1, or the rapalog temsirolimus were evaluated in TNBC cell lines. Synergy was assessed using the combination index method of Chou and Talalay. We utilized reverse-phase protein array to map the signaling architecture of the treated lines to verify target suppression and identify pharmacodynamic biomarkers. Results: All combinations demonstrated synergy that was mediated by both suppression of proliferation and cell death in a dose-dependent manner. Cell death was delayed, peaking at least 96 hours post-dosing, and was associated with sustained suppression of target proteins in both pathways, including pERKT202/Y204, pS6rpS235/236, p4EBP-1S65, and pPRAS40T246. However, suppression of pAKT (at T308 or S473) was variable and not consistently required for cell death. Pathway mapping identified a protein network ‘signature’ specific to all combination therapies that emerged at 72 hours and was associated with cell death. Thus, all combinations appear to share common downstream effectors. All combinations showed promising efficacy and will be evaluated in a human-in-mouse model of TNBC. Conclusions: These data support therapeutic strategies for TNBC that simultaneously inhibit both arms of the MAPK/PI3K/mTOR signaling network. For continued biomarker development, we stress the importance of studying the delayed effects of combination therapy. This strategy coupled with a protein network based approach uncovered a unique functional signaling ‘signature’.
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STEFANELLI, Claudio, Francesca BONAVITA, Ivana STANIC', Giovanna FARRUGGIA, Elisabetta FALCIERI, Iole ROBUFFO, Carla PIGNATTI, et al. "ATP depletion inhibits glucocorticoid-induced thymocyte apoptosis." Biochemical Journal 322, no. 3 (March 15, 1997): 909–17. http://dx.doi.org/10.1042/bj3220909.
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In quiescent thymocytes, mitochondrial de-energization was not correlated to apoptotic death. In fact, thymocytes treated with oligomycin, a highly specific inhibitor of ATP synthase, alone or with atractyloside to block ATP translocation from the cytoplasm, were alive, even if their mitochondria were depolarized, as revealed by flow cytometry after Rhodamine 123 staining. Furthermore, oligomycin was a powerful inhibitor of apoptosis induced in rat thymocytes by dexamethasone and, to a lesser extent, by the calcium ionophore A23187 and etoposide, but was without effect when apoptosis was induced by staurosporine, and increased cell death in mitogen-treated thymocytes. The inhibition of apoptosis was confirmed by morphological criteria, inhibition of inter-nucleosomal DNA fragmentation and inhibition of the loss of membrane integrity. The anti-apoptotic effect of oligomycin in cells treated with A23187 or etoposide was correlated to the inhibition of protein synthesis, while inhibition of apoptosis induced by dexamethasone, already evident at an oligomycin concentration of 10 ng/ml, was instead strictly correlated to the effect exerted on the cellular ATP level. Thymocyte apoptosis triggered by dexamethasone was blocked or delayed by inhibitors of respiratory-chain uncouplers, inhibitors of ATP synthase and antioxidants: a lasting protection from dexamethasone-induced apoptosis was always correlated to a drastic and rapid reduction in ATP level (31–35% of control), while a delay in the death process was characterized by a moderate decrease in ATP (73–82% of control). Oligomycin inhibited the specific binding of radioactive corticosteroid to thymocyte nuclei, confirming the inhibitory effect of ATP depletion on glucocorticoid binding and suggesting that ATP depletion is a common mediator of the anti-apoptotic action of different effectors in glucocorticoid-induced apoptosis. In conclusion, the reported data indicate that ATP may act as a cellular modulator of some forms of apoptosis, depending on the death trigger, and that in quiescent cells the de-energization of mitochondria is not necessarily linked to apoptosis.
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Hilton, Genell D., Bogdan A. Stoica, Kimberly R. Byrnes, and Alan I. Faden. "Roscovitine Reduces Neuronal Loss, Glial Activation, and Neurologic Deficits after Brain Trauma." Journal of Cerebral Blood Flow & Metabolism 28, no. 11 (July 9, 2008): 1845–59. http://dx.doi.org/10.1038/jcbfm.2008.75.
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Traumatic brain injury (TBI) causes both direct and delayed tissue damage. The latter is associated with secondary biochemical changes such as cell cycle activation, which leads to neuronal death, inflammation, and glial scarring. Flavopiridol—a cyclin-dependent kinase (CDK) inhibitor that is neither specific nor selective—is neuroprotective. To examine the role of more specific CDK inhibitors as potential neuroprotective agents, we studied the effects of roscovitine in TBI. Central administration of roscovitine 30 mins after injury resulted in significantly decreased lesion volume, as well as improved motor and cognitive recovery. Roscovitine attenuated neuronal death and inhibited activation of cell cycle pathways in neurons after TBI, as indicated by attenuated cyclin G1 accumulation and phosphorylation of retinoblastoma protein. Treatment also decreased microglial activation after TBI, as reflected by reductions in ED1, galectin-3, p22PHOX, and Iba-1 levels, and attenuated astrogliosis, as shown by decreased accumulation of glial fibrillary acidic protein. In primary cortical microglia and neuronal cultures, roscovitine and other selective CDK inhibitors attenuated neuronal cell death, as well as decreasing microglial activation and microglial-dependent neurotoxicity. These data support a multifactorial neuroprotective effect of cell cycle inhibition after TBI—likely related to inhibition of neuronal apoptosis, microglial-induced inflammation, and gliosis—and suggest that multiple CDKs are potentially involved in this process.
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Fu, Shengya, Ting Wang, and Feng Xu. "Delayed immune thrombocytopenia after discontinuation of nivolumab therapy: A case report and literature review." Journal of Oncology Pharmacy Practice 27, no. 6 (January 12, 2021): 1548–52. http://dx.doi.org/10.1177/1078155220981155.
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Introduction Nivolumab, a programmed death-1(PD-1) inhibitor antibody, have demonstrated anti-tumor activity for multiple malignancies. Such immune checkpoint inhibitors induce novel and distinctive adverse effects, which are collectively named immune-related adverse events. Immune-related adverse events can theoretically occur at any part of the body, including the haemopoietic system. Most immune-related adverse events developed within 10 weeks of receiving immunotherapy. Thus far, there is no report of immune thrombocytopenia as an immune-related adverse event developed after discontinuation of immunotherapy. Case report We describe a 62-year-old male with metastatic non-small cell lung cancer developed immune thrombocytopenia nearly two months after discontinuation of nivolumab. When thrombocytopenia was detected, the patient was undergoing radiotherapy of supraclavicular lymph nodes. After complex diagnosis-by-exclusion process, nivolumab-induced immune thrombocytopenia was diagnosed. Management and outcome Intravenous immunoglobulins 20 g daily for 5 days, intravenous methylprednisolone 40 mg daily for 14 days followed by oral prednisone, intermittent platelet transfusion and oral thrombopoietin receptor (eltrombopag 25 mg daily) were administered. After 30 days, his platelet count had achieved a level of adequate hemostasis and continued to improvement during the tapering period. Discussion Most immune-related developed 6 months of immunotherapy. Clinicians need to be aware of a clinical diagnostic complex, developing months to years after discontinuation of immunotherapy, which recently is termed delayed immune-related events. This case is the first report of immune checkpoint inhibitors-induced thrombocytopenia that developed nearly 2 months after discontinuation of treatment with nivolumab for metastatic NSCLC. In future clinical practice, patients who have received immune checkpoint inhibitors develop new or unexplained symptom, irrespective of interval post-immunotherapy, immune-related adverse events should be considered.
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Ying, Weihai, Yongmei Chen, Conrad C. Alano, and Raymond A. Swanson. "Tricarboxylic Acid Cycle Substrates Prevent PARP-Mediated Death of Neurons and Astrocytes." Journal of Cerebral Blood Flow & Metabolism 22, no. 7 (July 2002): 774–79. http://dx.doi.org/10.1097/00004647-200207000-00002.
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The DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), contributes to cell death during ischemia/reperfusion when extensively activated by DNA damage. The cell death resulting from PARP1 activation is linked to NAD+ depletion and energy failure, but the intervening steps are not well understood. Because glycolysis requires cytosolic NAD+, the authors tested whether PARP1 activation impairs glycolytic flux and whether substrates that bypass glycolysis can rescue cells after PARP1 activation. PARP1 was activated in mouse cortical astrocyte and astrocyte-neuron cocultures with the DNA alkylating agent, N-methyl- N ′-nitro- N-nitrosoguanidine (MNNG). Studies using the 2-deoxyglucose method confirmed that glycolytic flux was reduced by more than 90% in MNNG-treated cultures. The addition of 5 mmol/L of α-ketoglutarate, 5 mmol/L pyruvate, or other mitochondrial substrates to the cultures after MNNG treatment reduced cell death from approximately 70% to near basal levels, while PARP inhibitors and excess glucose had negligible effects. The mitochondrial substrates significantly reduced cell death, with delivery delayed up to 2 hours after MNNG washout. The findings suggest that impaired glycolytic flux is an important factor contributing to PARP1-mediated cell death. Delivery of alternative substrates may be a promising strategy for delayed treatment of PARP1-mediated cell death in ischemia and other disorders.
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White, Michael G., Osama Saleh, Doris Nonner, Ellen F. Barrett, Carlos T. Moraes, and John N. Barrett. "Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons." Journal of Neurophysiology 108, no. 8 (October 15, 2012): 2203–14. http://dx.doi.org/10.1152/jn.00638.2011.
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Previous work demonstrated that hyperthermia (43°C for 2 h) results in delayed, apoptotic-like death in striatal neuronal cultures. We investigated early changes in mitochondrial function induced by this heat stress. Partial depolarization of the mitochondrial membrane potential (ΔΨm) began about 1 h after the onset of hyperthermia and increased as the stress continued. When the heat stress ended, there was a partial recovery of ΔΨm, followed hours later by a progressive, irreversible depolarization of ΔΨm. During the heat stress, O2 consumption initially increased but after 20–30 min began a progressive, irreversible decline to about one-half the initial rate by the end of the stress. The percentage of oligomycin-insensitive respiration increased during the heat stress, suggesting an increased mitochondrial leak conductance. Analysis using inhibitors and substrates for specific respiratory chain complexes indicated hyperthermia-induced dysfunction at or upstream of complex I. ATP levels remained near normal for ∼4 h after the heat stress. Mitochondrial movement along neurites was markedly slowed during and just after the heat stress. The early, persisting mitochondrial dysfunction described here likely contributes to the later (>10 h) caspase activation and neuronal death produced by this heat stress. Consistent with this idea, proton carrier-induced ΔΨm depolarizations comparable in duration to those produced by the heat stress also reduced neuronal viability. Post-stress ΔΨm depolarization and/or delayed neuronal death were modestly reduced/postponed by nicotinamide adenine dinucleotide, a calpain inhibitor, and increased expression of Bcl-xL.
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Endres, Matthias, Shobu Namura, Masao Shimizu-Sasamata, Christian Waeber, Lin Zhang, Teresa Gómez-Isla, Bradley T. Hyman, and Michael A. Moskowitz. "Attenuation of Delayed Neuronal Death after Mild Focal Ischemia in Mice by Inhibition of the Caspase Family." Journal of Cerebral Blood Flow & Metabolism 18, no. 3 (March 1998): 238–47. http://dx.doi.org/10.1097/00004647-199803000-00002.
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Inhibitors of apoptosis and of excitotoxic cell death reduce brain damage after transient and permanent middle cerebral artery occlusion. We compared the neuroprotective effects of two caspase family inhibitors with the N-methyl-d-aspartate receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in a newly characterized cycloheximidesensitive murine model of transient middle cerebral artery occlusion (30 minutes) in which apoptotic cell death is prominent. Ischemic infarction, undetected by 2,3,5-triphenyltetrazolium chloride staining at 24-hour reperfusion, featured prominently in the striatum at 72 hours and 7 days on hematoxylin-eosin—stained sections. Markers of apoptosis, such as oligonucleosomal DNA damage (laddering) and terminal deoxynucleotidyl transferase—mediated dUTP-biotin nick-end labeling (TUNEL)–positive cells first appeared at 24 hours and increased significantly at 72 hours and 7 days after reperfusion. The TUNEL-labeled cells were mostly neurons and stained negative for glial (GFAP, glial fibrillary acid protein) and leukocyte specific markers (CD-45). The caspase inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.FMK; 120 ng intracerebroventricularly) or N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone (z-DEVD.FMK; 480 ng intracerebroventricularly) decreased infarct size and neurologic deficits when administered 6 hours after reperfusion. The extent of protection was greater than in models of more prolonged ischemia or after permanent occlusion, and the therapeutic window was extended from 0 to 1 hours after 2-hour middle cerebral artery occlusion to at least 6 hours after brief ischemia. Also, z-VAD.FMK and z-DEVD.FMK treatment decreased oligonucleosomal DNA damage (DNA laddering) as assessed by quantitative autoradiography after gel electrophoresis. By contrast, MK-801 protected brain tissue only when given before ischemia (3 mg/kg intraperitoneally), but not at 3 or 6 hours after reperfusion. Despite a decrease in infarct size after MK-801 pretreatment, the amount of DNA laddering did not decrease 72 hours after reperfusion, thereby suggesting a mechanism distinct from inhibition of apoptosis. Hence, 30 minutes of reversible ischemia augments apoptotic cell death, which can be attenuated by delayed z-VADPMK and z-DEVD.FMK administration with preservation of neurologic function. By contrast, the therapeutic window for MK-801 does not extend beyond the time of occlusion, probably because its primary mechanism of action does not block the development of apoptotic cell death.
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Finnegan, Ryan Michael. "Abstract P1-13-02: Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–13–02—P1–13–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-13-02.
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Abstract While anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer, relapse after remission continues to be a serious limitation to the effectiveness of these therapies. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into a state of autophagy/senescence from which a subpopulation ultimately escapes, potentially contributing to disease recurrence. ER+ MCF-7 breast tumor cells that were induced into autophagy/senescence by Fulvestrant + Palbociclib in vitro were exposed to the autophagy inhibitors, chloroquine and bafilomycin, prior to as well as after growth arrest. However, autophagy inhibition only moderately enhanced the response to therapy and, at best, delayed proliferative recovery. These findings were confirmed by genetic inhibition of autophagy. Despite clear entry into a state of senescence, the Bcl-xl inhibitor and senolytic ABT-263 (navitoclax) failed to promote tumor cell death; this is likely a consequence of high levels of survivin in the MCF-7 breast tumor cell line. However, the BET inhibitor, ARV-825, eliminated a large fraction of the senescent cell population and significantly delayed proliferative recovery. Cell death did not appear to be a consequence of increased apoptosis. Additionally, analysis of three database sets demonstrated that higher breast cancer expression of BRD4, a primary target of ARV-825, correlated with lower recurrence-free survival compared to patients with cancers expressing lower levels of BRD4. These studies indicate that administration of BET inhibitors, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients by prolonging progression-free survival. Citation Format: Ryan Michael Finnegan. Autophagy inhibition and senolytics to improve the response to fulvestrant + palbociclib in ER positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-02.
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Kohno, Keiji, Shinsuke Ohta, Shigeru Furuta, Kanehisa Kohno, Yoshiaki Kumon, and Saburo Sakaki. "Intraventricular administration of nitric oxide synthase inhibitors prevents delayed neuronal death in gerbil hippocampal CA 1 neurons." Neuroscience Letters 199, no. 1 (October 1995): 65–68. http://dx.doi.org/10.1016/0304-3940(95)12018-y.
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Erkkila, Krista, Sauli Kyttanen, Marten Wikstrom, Kimmo Taari, Amiya P. Sinha Hikim, Ronald S. Swerdloff, and Leo Dunkel. "Regulation of human male germ cell death by modulators of ATP production." American Journal of Physiology-Endocrinology and Metabolism 290, no. 6 (June 2006): E1145—E1154. http://dx.doi.org/10.1152/ajpendo.00142.2005.
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The understanding of testicular physiology, pathology, and male fertility issues requires knowledge of male germ cell death and energy production. Here, we induced human male germ cell apoptosis (detected by Southern blot analysis of DNA fragmentation, TUNEL, activation of caspases-3 and -9, and electron microscopy) by incubating seminiferous tubule segments under hormone- and serum-free conditions. Inhibitors of complexes I to IV of mitochondrial respiration, exposure to anoxia, and inhibition of F0F1-ATPase (with oligomycin) decreased the ATP levels (analyzed by HPLC) and suppressed apoptosis at 4 h. Uncoupler 2,4-dinitrophenol (DNP) and oligomycin combination also suppressed death at 4 h, as did the DNP alone. Inhibition of glycolysis by 2-deoxyglucose neither suppressed nor further induced apoptosis nor altered the antiapoptotic effects of the mitochondrial inhibitors. Furthermore, Fas system activation did not modify the effects of mitochondrial modulators. After 24 h, delayed male germ cell apoptosis was observed despite the presence of the mitochondrial inhibitors. We conclude that the mitochondrial ATP production machinery plays an important role in regulating in vitro-induced primary pathways of human male germ apoptosis. The ATP synthesized by the F0F1-ATPase seems to be the crucial death regulator, rather than any of the complexes (I-IV) alone, the functional electron transport chain, or the membrane potential. We also conclude that there seem to be secondary pathways of human testicular cell apoptosis that do not require mitochondrial ATP production. The present study emphasizes the role of the main catabolic pathways in the complex network of regulating events of male germ cell life and death.
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Koponen, Susanna, Gundars Goldsteins, Riitta Keinänen, and Jari Koistinaho. "Induction of Protein Kinase Cδ Subspecies in Neurons and Microglia after Transient Global Brain Ischemia." Journal of Cerebral Blood Flow & Metabolism 20, no. 1 (January 2000): 93–102. http://dx.doi.org/10.1097/00004647-200001000-00013.
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The delayed death of CA1 neurons after global brain ischemia is associated with induction of apoptosis genes and is inhibited by protein synthesis inhibitors, suggesting that the degeneration of CA1 pyramidal neurons is an active process that requires new gene expression. The transient global ischemia model has been extensively used to identify enzymes and other proteins underlying delayed neuronal cell death. The expression of protein kinase C (PKC) subspecies after 20 minutes of global brain ischemia produced by a four-vessel occlusion model in the rat was studied. From the multiple PKC subspecies studied, only PKCδ mRNA was significantly up-regulated in CA1 pyramidal neurons at 24 hours and in activated microglia at 3 to at least 7 days after ischemia. The induction of PKCδ mRNA was also found in the cortex at 8 hours and 3 days after ischemia. This cortical but not hippocampal induction was regulated by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate receptor antagonist, 6-nitro-7-sulfamobenzo[ f]quinoxaline-2,3-dione, and glucocorticoids. An N-methyl-d-aspartate receptor antagonist, MK-801, was without effect on the induction of PKCδ subspecies. The selective and prolonged induction of the PKCδ mRNA and protein first in CA1 pyramidal neurons and at a later stage in activated microglia suggests that the PKCδ isozyme may take part in regulation of the delayed death of CA1 neurons after transient global brain ischemia.
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Hutson, Thomas E., Frank Xiaoqing Liu, Shivani Pandya, Christopher Dieyi, Ruth Kim, Stan Krulewicz, Vijay Kasturi, and Abhijeet Bhanegaonkar. "Clinical impact of early progression among patients (Pts) with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs) in first-line (1L) setting: IMPACT RCC real-world study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e17079-e17079. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17079.
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e17079 Background: Previous research has indicated a high burden of illness among mRCC pts who progressed to second line (2L) systemic therapy, suggesting benefits to delaying 1L progression. This study examined the clinical impact of early vs delayed disease progression among mRCC pts treated with 1L TKI monotherapies followed by 2L therapy in the US Veterans Health Administration (VHA) database. Methods: Newly diagnosed mRCC pts treated with 1L TKIs followed by 2L therapy were identified between OCT2013-MAR2018 within the VHA database (1L start date = index date). Eligible pts were required to have continuous enrollment for ≥6 months post-2L therapy initiation unless the pt died. A Kaplan-Meier (KM)-derived median time to 2L therapy initiation was used as the cut-off to categorize pts into early (≤median) and delayed ( > median) progression cohorts. KM analysis and Cox proportional hazards models were used to compare and assess the impact of predictive factors on clinical outcomes including overall survival (OS), time to 2L discontinuation (index date to 2L discontinuation or death), and time to 3L treatment initiation (index date to 3L start or death) among pts in the early vs delayed progression cohorts. Results: Among 289 mRCC pts, the mean age was 67.4 years and the median time to 2L initiation was 6.1 months. Pt characteristics were similar between the early (n = 145) and delayed (n = 144) progression cohorts. During follow-up, the delayed progression cohort had better clinical outcomes than the early progression cohort did (Table below). Conclusions: Early progression is associated with worse clinical outcomes, confirming the need to delay disease progression among mRCC pts with effective 1L treatment strategies. Results indicate the need for use of more efficacious therapies, e.g. immuno-oncology-based combinations, in 1L that can delay disease progression and have potential to reduce disease burden. [Table: see text]
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Dawson, T. L., G. J. Gores, A. L. Nieminen, B. Herman, and J. J. Lemasters. "Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes." American Journal of Physiology-Cell Physiology 264, no. 4 (April 1, 1993): C961—C967. http://dx.doi.org/10.1152/ajpcell.1993.264.4.c961.
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Cell killing, oxygen consumption, and hydroperoxide formation were determined in rat hepatocytes after glycolytic and respiratory inhibition. These conditions model the ATP depletion and reductive stress of anoxia (“chemical hypoxia”). Glycolysis was inhibited with iodoacetate, and mitochondrial electron transfer was blocked with sodium azide, cyanide, or myxothiazol. Cell killing, hydroperoxide formation, and inhibitor-insensitive oxygen consumption were greater after azide than after myxothiazol or cyanide. Desferrioxamine, an inhibitor of iron-catalyzed hydroxyl radical formation, delayed cell killing after each of the respiratory inhibitors. Anoxia also delayed cell killing during chemical hypoxia. However, during anoxic incubations, desferrioxamine did not delay the onset of cell death. These findings indicate that reactive oxygen species participate in lethal cell injury during chemical hypoxia. In isolated mitochondria, previous studies have shown that myxothiazol inhibits Q cycle-mediated ubisemiquinone formation in complex III (ubiquinol-cytochrome c oxidoreductase) and that ubisemiquinone can react with molecular oxygen to form superoxide. Decreased killing of hepatocytes with myxothiazol compared with azide suggests, therefore, that mitochondrial oxygen radical formation by complex III is involved in cell killing during reductive stress. In support of this hypothesis, myxothiazol reduced rates of cell killing and hydroperoxide formation in hepatocytes incubated with azide or cyanide. This mitochondrial mechanism for oxygen radical formation may be important in relative but not absolute hypoxia.
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Péron, Julien, Alexandre Lambert, Stephane Munier, Brice Ozenne, Joris Giai, Pascal Roy, Stéphane Dalle, Abigirl Machingura, Delphine Maucort-Boulch, and Marc Buyse. "Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit." JNCI: Journal of the National Cancer Institute 111, no. 11 (March 5, 2019): 1186–91. http://dx.doi.org/10.1093/jnci/djz030.
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Abstract Background The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death. Methods The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed. Results In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance. Conclusion The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.
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Shinzawa, Koei, and Yoshihide Tsujimoto. "PLA2 activity is required for nuclear shrinkage in caspase-independent cell death." Journal of Cell Biology 163, no. 6 (December 15, 2003): 1219–30. http://dx.doi.org/10.1083/jcb.200306159.
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Apoptosis is defined on the basis of morphological changes like nuclear fragmentation and chromatin condensation, which are dependent on caspases. Many forms of caspase-independent cell death have been reported, but the mechanisms are still poorly understood. We found that hypoxic cell death was independent of caspases and was associated with significant nuclear shrinkage. Neither Bcl-2 nor Apaf-1 deficiency prevented hypoxic nuclear shrinkage. To understand the molecular mechanism of the nuclear shrinkage, we developed an in vitro system using permeabilized cells, which allowed us to purify a novel member of the phospholipase A2 (PLA2) family that induced nuclear shrinkage. Purified PLA2 induced nuclear shrinkage in our permeabilized cell system. PLA2 inhibitors prevented hypoxic nuclear shrinkage in cells and cell death. Hypoxia caused elevation of PLA2 activity and translocation of intracellular PLA2s to the nucleus. Knockdown of the Ca2+-independent PLA2 delayed nuclear shrinkage and cell death. These results indicate that Ca2+-independent PLA2 is crucial for a caspase-independent cell death signaling pathway leading to nuclear shrinkage.
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Yan, Jie, Alexander Günter, Soumyaparna Das, Regine Mühlfriedel, Stylianos Michalakis, Kangwei Jiao, Mathias W. Seeliger, and François Paquet-Durand. "Inherited Retinal Degeneration: PARP-Dependent Activation of Calpain Requires CNG Channel Activity." Biomolecules 12, no. 3 (March 15, 2022): 455. http://dx.doi.org/10.3390/biom12030455.
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Inherited retinal degenerations (IRDs) are a group of blinding diseases, typically involving a progressive loss of photoreceptors. The IRD pathology is often based on an accumulation of cGMP in photoreceptors and associated with the excessive activation of calpain and poly (ADP-ribose) polymerase (PARP). Inhibitors of calpain or PARP have shown promise in preventing photoreceptor cell death, yet the relationship between these enzymes remains unclear. To explore this further, organotypic retinal explant cultures derived from wild-type and IRD-mutant mice were treated with inhibitors specific for calpain, PARP, and voltage-gated Ca2+ channels (VGCCs). The outcomes were assessed using in situ activity assays for calpain and PARP and immunostaining for activated calpain-2, poly (ADP-ribose), and cGMP, as well as the TUNEL assay for cell death detection. The IRD models included the Pde6b-mutant rd1 mouse and rd1*Cngb1−/− double-mutant mice, which lack the beta subunit of the rod cyclic nucleotide-gated (CNG) channel and are partially protected from rd1 degeneration. We confirmed that an inhibition of either calpain or PARP reduces photoreceptor cell death in rd1 retina. However, while the activity of calpain was decreased by the inhibition of PARP, calpain inhibition did not alter the PARP activity. A combination treatment with calpain and PARP inhibitors did not synergistically reduce cell death. In the slow degeneration of rd1*Cngb1−/− double mutant, VGCC inhibition delayed photoreceptor cell death, while PARP inhibition did not. Our results indicate that PARP acts upstream of calpain and that both are part of the same degenerative pathway in Pde6b-dependent photoreceptor degeneration. While PARP activation may be associated with CNG channel activity, calpain activation is linked to VGCC opening. Overall, our data highlights PARP as a target for therapeutic interventions in IRD-type diseases.
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Zhang, Yunhong, Xiaochun Zhang, Tae S. Park, and Jeffrey M. Gidday. "Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation." Journal of Cerebral Blood Flow & Metabolism 25, no. 7 (February 23, 2005): 868–77. http://dx.doi.org/10.1038/sj.jcbfm.9600081.
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Cerebral ischemia-reperfusion leads to vascular dysfunction characterized by endothelial cell injury or death. In the present study, we used an in vitro model to elucidate mechanisms of human brain microvascular endothelial cell (HBMEC) injury after episodic ischemia-reperfusion. Near-confluent HBMEC cultures were exposed to intermittent hypoxia-reoxygenation (HX/RO) and, at different recovery time points, cell viability was assessed by the MTT assay, apoptotic death by fluorescence microscopy of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL)-positive cells, and nuclear translocation of apoptosis-inducing factor (AIF) and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) by immunoblotting of subcellular fractions. Reductions in HBMEC viability were proportional to the number of HX/RO cycles, and not the total duration of hypoxia. Using four cycles of 1-h HX with 1 h of intervening normoxic RO, cell viability was reduced 30% to 40% between 12 and 48 h. Treatment with the PARP-1 inhibitors 3-aminobenzamide or 4-amino-1,8-naphthalimide during the insult improved HBMEC viability at 24 h after insult, and resulted in dose-dependent reductions in TUNEL-positivity at 16 h after insult, but not if these treatments were delayed by 4 h. HX/RO-induced increases in nuclear AIF translocation, as well as PARP-1 cleavage, were also reduced dose-dependently at 4 h after insult by the inhibitors. The caspase inhibitor z-VAD-fmk blocked PARP-1 cleavage, but did not affect AIF translocation and was only modestly cytoprotective. These findings indicate that PARP-1 activation and a PARP-1-dependent, caspase-independent, nuclear translocation of AIF contribute to apoptotic cerebral endothelial cell death after ischemia-reperfusion, underscoring the potential for ischemic microvascular protection by inhibiting PARP activation or preventing AIF translocation.
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Bommareddy, Praveen K., Salvatore Aspromonte, Andrew Zloza, Samuel D. Rabkin, and Howard L. Kaufman. "MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation." Science Translational Medicine 10, no. 471 (December 12, 2018): eaau0417. http://dx.doi.org/10.1126/scitranslmed.aau0417.
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Melanoma is an aggressive cutaneous malignancy, but advances over the past decade have resulted in multiple new therapeutic options, including molecularly targeted therapy, immunotherapy, and oncolytic virus therapy. Talimogene laherparepvec (T-VEC) is a herpes simplex type 1 oncolytic virus, and trametinib is a MEK inhibitor approved for treatment of melanoma. Therapeutic responses with T-VEC are often limited, and BRAF/MEK inhibition is complicated by drug resistance. We observed that the combination of T-VEC and trametinib resulted in enhanced melanoma cell death in vitro. Further, combination treatment resulted in delayed tumor growth and improved survival in mouse models. Tumor regression was dependent on activated CD8+ T cells and Batf3+ dendritic cells. We also observed antigen spreading and induction of an inflammatory gene signature, including increased expression of PD-L1. Triple therapy with the combination of T-VEC, MEK inhibition, and anti–PD-1 antibody further augmented responses. These data support clinical development of combination oncolytic viruses, MEK inhibitors, and checkpoint blockade in patients with melanoma.
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Burdova, Kamila, Radka Storchova, Matous Palek, and Libor Macurek. "WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors." Cells 8, no. 10 (October 15, 2019): 1258. http://dx.doi.org/10.3390/cells8101258.
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Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.
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Liu, Yongqing, Pengbo Hu, Liang Xu, Xiuyuan Zhang, Zhou Li, Yiming Li, and Hong Qiu. "Current Progress on Predictive Biomarkers for Response to Immune Checkpoint Inhibitors in Gastric Cancer: How to Maximize the Immunotherapeutic Benefit?" Cancers 15, no. 8 (April 13, 2023): 2273. http://dx.doi.org/10.3390/cancers15082273.
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Gastric cancer is the fifth most prevalent cancer and the fourth leading cause of cancer death globally. Delayed diagnosis and pronounced histological and molecular variations increase the complexity and challenge of treatment. Pharmacotherapy, which for a long time was systemic chemotherapy based on 5-fluorouracil, is the mainstay of management for advanced gastric cancer. Trastuzumab and programmed cell death 1 (PD-1) inhibitors have altered the therapeutic landscape, contributing to noticeably prolonged survivorship in patients with metastatic gastric cancer. However, research has revealed that immunotherapy is only beneficial to some individuals. Biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and tumor mutational load (TMB), have been shown to correlate with immune efficacy in numerous studies and are increasingly employed for the selection of patients most likely to respond to immunotherapy. Gut microorganisms, genetic mutations like POLE/POLD1 and NOTCH4, tumor lymphoid infiltrating cells (TILs), and other novel biomarkers have the potential to develop into new predictors. Prospective immunotherapy for gastric cancer should be guided by a biomarker-driven precision management paradigm, and multidimensional or dynamic marker testing could be the way to go.
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Vucic, D., S. Seshagiri, and L. K. Miller. "Characterization of reaper- and FADD-induced apoptosis in a lepidopteran cell line." Molecular and Cellular Biology 17, no. 2 (February 1997): 667–76. http://dx.doi.org/10.1128/mcb.17.2.667.
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Expression of the reaper gene (rpr) correlates with the initiation of apoptosis in Drosophila melanogaster. Transient expression of rpr in the lepidopteran SF-21 cell line induced apoptosis displaying nuclear condensation and fragmentation, oligonucleosomal ladder formation, cell surface blebbing, and apoptotic body formation. Inhibitors of ICE-family proteases p35 and crmA, as well as members of the iap class of genes, Op-iap and D-iap2, but not bcl-2 family members, blocked rpr-induced apoptosis. Mutational analysis of rpr provided no support for the proposed sequence similarity of Reaper and death domain proteins. Mutations in the N-terminal region of Reaper, which displays sequence similarity to Hid and Grim, other Drosophila gene products correlated with the initiation of apoptosis, suggested that these residues might be functionally important. The mammalian cDNA encoding FADD (Fas-associating protein with a death domain) also induced cell death in SF-21 cells, but death progressed more slowly and with features which distinguished it from rpr-induced apoptosis. Several bcl-2 family members delayed or blocked FADD-induced cellular death. Thus, apoptosis initiated by Reaper progressed by a faster path which appeared to differ from that of FADD-induced apoptosis.
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Ellis, Leigh, Michael Bots, Ralph K. Lindemann, Jessica E. Bolden, Andrea Newbold, Leonie A. Cluse, Clare L. Scott, et al. "The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy." Blood 114, no. 2 (July 9, 2009): 380–93. http://dx.doi.org/10.1182/blood-2008-10-182758.
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Abstract LAQ824 and LBH589 (panobinostat) are histone deacetylase inhibitors (HDACi) developed as cancer therapeutics and we have used the Eμ-myc lymphoma model to identify the molecular events required for their antitumor effects. Induction of tumor cell death was necessary for these agents to mediate therapeutic responses in vivo and both HDACi engaged the intrinsic apoptotic cascade that did not require p53. Death receptor pathway blockade had no effect on the therapeutic activities of LAQ824 and LBH589; however, overexpression of Bcl-2 or Bcl-XL protected lymphoma cells from HDACi-induced killing and suppressed their therapeutic activities. Deletion of Apaf-1 or Caspase-9 delayed HDACi-induced lymphoma killing in vitro and in vivo, associated with suppression of many biochemical indicators of apoptosis, but did not provide long-term resistance to these agents and failed to inhibit their therapeutic activities. Eμ-myc lymphomas lacking a functional apoptosome displayed morphologic and biochemical features of autophagy after treatment with LAQ824 and LBH589, indicating that, in the absence of a complete intrinsic apoptosis pathway involving apoptosome formation, these HDACi can still mediate a therapeutic response. Our data indicate that damage to the mitochondria is the key event necessary for LAQ824 and LBH589 to mediate tumor cell death and a robust therapeutic response.
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Vogel, Peter, Herman v. d. Putten, Erik Popp, Jakub J. Krumnikl, Peter Teschendorf, Roland Galmbacher, Malgorzata Kisielow, et al. "Improved Resuscitation after Cardiac Arrest in Rats Expressing the Baculovirus Caspase Inhibitor Protein p35 in Central Neurons." Anesthesiology 99, no. 1 (July 1, 2003): 112–21. http://dx.doi.org/10.1097/00000542-200307000-00020.
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Background Global cerebral ischemia is associated with delayed neuronal death. Given the role of caspases in apoptosis, caspase inhibitors may provide neuronal protection after cardiac arrest. To this end, the authors generated a transgenic rat line expressing baculovirus p35, a broad-spectrum caspase inhibitor, in central neurons. Its effects were evaluated on neuronal cell death and outcome after global cerebral ischemia. Methods Global cerebral ischemia was induced by cardiocirculatory arrest. After 6 min, animals were resuscitated by controlled ventilation, extrathoracic cardiac massage, epinephrine, and electrical countershocks. Neuronal death was assessed after 7 days by histologic evaluation of the hippocampal cornu ammonis 1 sector. Postischemic outcome was assessed by determination of overall survival and according to neurologic deficit scores 24 h, 3 days, and 7 days after resuscitation. Results The rate of 7-day survival after cardiac arrest for the transgenic rats (85%) was significantly higher than that for the nontransgenic controls (52%; P < 0.05). However, no differences were observed either in the number of terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling-positive cells or viable neurons in the cornu ammonis 1 sector or in the neurologic deficit score when comparing surviving transgenic and nontransgenic rats. These findings suggest that neuronal apoptosis after cardiac arrest is not primarily initiated by activation of caspases. Conclusion Expression of baculovirus p35 can improve survival after cardiac arrest in rats, but the mode and site of action remain to be elucidated.
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Smith, M. W., P. C. Phelps, and B. F. Trump. "Injury-induced changes in cytosolic Ca2+ in individual rabbit proximal tubule cells." American Journal of Physiology-Renal Physiology 262, no. 4 (April 1, 1992): F647—F655. http://dx.doi.org/10.1152/ajprenal.1992.262.4.f647.
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Cell injury was studied in cultured rabbit proximal tubular epithelial cells using digital-imaging fluorescent microscopy to relate changes in cytosolic Ca2+ ([Ca2+]i) to bleb formation and cell death. Fura-2-loaded cells were treated in normal (1.37 mM) and low (less than 5 microM) extracellular Ca2+ ([Ca2+]e) with 1) inhibitors of glycolysis (iodoacetate) and/or mitochondrial oxidation (KCN), 2) thiol-modifying reagents (N-ethylmaleimide, p-chloromercuribenzene, and p-chloromercuribenzene sulfonate), and 3) Ca2+ ionophore (ionomycin). All three types of injury produced both [Ca2+]e-independent and [Ca2+]e-dependent increases in [Ca2+]i. KCN + iodoacetate +/- [Ca2+]e did not produce blebbing or death within 60-90 min. Thiol modifiers and ionomycin produced blebbing, which correlated with sustained threefold or greater elevations of [Ca2+]i and loss of viability only after [Ca2+]i had risen severalfold. Blebbing and cell death could be prevented or delayed by treatment in low [Ca2+]e. Trypsin (x0.5) caused a transient (less than 5 min) elevation in [Ca2+]i as well as increases in intracellular Ca2+ pools.
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Neuendorff, Nina Rosa. "Therapie-assoziierte myeloische Neoplasien: Woran bei Blutbildveränderungen unter Therapie mit PARP-Inhibitoren gedacht werden sollte." Kompass Onkologie 9, no. 1 (2022): 20–21. http://dx.doi.org/10.1159/000522397.
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<b>Background:</b> Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor-related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO’s pharmacovigilance database (VigiBase). <b>Methods:</b> We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age ≥18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023. <b>Findings:</b> For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n = 7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2·63 [95% CI 1·13–6·14], p = 0·026) with no between-study heterogeneity (I2 = 0%, χ2 p = 0·91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0·73% (95% CI 0·50–1·07; I2 = 0%, χ2 p = 0·87; 21 events out of 4533 patients) and across placebo groups was 0·47% (0·26–0·85; I2 = 0%, χ2 p = 1·00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n = 99) and acute myeloid leukaemia (n = 79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9·8 months (IQR 3·6–17·4; n = 96) and median latency period since first exposure to a PARP inhibitor was 17·8 months (8·4–29·2; n = 58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. <b>Interpretation:</b> PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. <b>Funding:</b> None.
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Wang, Tzu-Fei, and Marc Carrier. "Immune Checkpoint Inhibitors-Associated Thrombosis: Incidence, Risk Factors and Management." Current Oncology 30, no. 3 (March 4, 2023): 3032–46. http://dx.doi.org/10.3390/curroncol30030230.
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Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality. While thrombosis was not reported as a major complication in initial clinical trials leading to the approval of ICIs, emerging evidence from post-marketing studies revealed concerning risks of thrombosis in patients receiving ICIs. However, results remained heterogenous given differences in study designs and populations. Recent studies also showed that C-reactive protein dynamics might be an easily accessible biomarker for thrombosis and disease response in this population. In addition, early findings indicated that a commonly used anticoagulant for cancer-associated thrombosis, factor Xa inhibitors, might have potential synergistic antitumor effects when combined with ICIs. Herein we will review the current literature on the incidence, risk factors, and management of thrombosis in patients with cancer receiving ICIs. We aim to provide valuable information for clinicians in managing these patients.
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Anderson, Jeffrey L., Kirk U. Knowlton, J. Brent Muhlestein, Tami L. Bair, Viet T. Le, and Benjamin D. Horne. "Evaluation of TReatment With Angiotensin Converting Enzyme Inhibitors and the Risk of Lung Cancer: ERACER—An Observational Cohort Study." Journal of Cardiovascular Pharmacology and Therapeutics 26, no. 4 (January 29, 2021): 321–27. http://dx.doi.org/10.1177/1074248420987054.
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Introduction: Angiotensin converting enzyme inhibitors (ACEIs) are widely prescribed medications. A recent British study reported a 14% increased risk of lung cancer with ACEI versus angiotensin receptor blocker (ARB) prescriptions, and risk increased with longer use. We sought to validate this observation. Methods: We searched the Intermountain Enterprise Data Warehouse from 1996 to 2018 for patients newly treated with an ACEI or an ARB and with ≥1 year’s follow-up or to incident lung cancer or death. Unadjusted and adjusted hazard ratios (HRs) for lung cancer and for lung cancer or all-cause mortality were calculated for ACEIs compared to ARBs. Results: A total of 187,060 patients met entry criteria (age 60.2 ± 15.1 y; 51% women). During a mean of 7.1 years follow-up (max: 20.0 years), 3,039 lung cancers and 43,505 deaths occurred. Absolute lung cancer rates were 2.16 and 2.31 per 1000 patient-years in the ARB and ACEI groups, respectively. The HR of lung cancer was modestly increased with ACEIs (unadjusted HR = 1.11, CI: 1.02, 1.22, P = .014; adjusted HR = 1.18, CI: 1.06, 1.31, P = .002; number needed to harm [NNH] 6,667). Rates of the composite of lung cancer or death over time also favored ARBs. Lung cancer event curves separated gradually over longitudinal follow-up beginning at 10-12 years. Conclusions: We noted a small long-term increase in lung cancer risk with ACEIs compared with ARBs. Separation of survival curves was delayed until 10-12 years after treatment initiation. Although the observed increases in lung cancer risk are small, implications are potentially important because of the broad use of ACEIs. Thus, additional work to validate these findings is needed.
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Katchanov, Juri, Christoph Harms, Karen Gertz, Ludger Hauck, Christian Waeber, Lorenz Hirt, Josef Priller, et al. "Mild Cerebral Ischemia Induces Loss of Cyclin-Dependent Kinase Inhibitors and Activation of Cell Cycle Machinery before Delayed Neuronal Cell Death." Journal of Neuroscience 21, no. 14 (July 15, 2001): 5045–53. http://dx.doi.org/10.1523/jneurosci.21-14-05045.2001.
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Fryknäs, Mårten, Linda Rickardson, Malin Wickström, Sumeer Dhar, Henrik Lövborg, Joachim Gullbo, Peter Nygren, Mats G. Gustafsson, Anders Isaksson, and Rolf Larsson. "Phenotype-Based Screening of Mechanistically Annotated Compounds in Combination with Gene Expression and Pathway Analysis Identifies Candidate Drug Targets in a Human Squamous Carcinoma Cell Model." Journal of Biomolecular Screening 11, no. 5 (April 28, 2006): 457–68. http://dx.doi.org/10.1177/1087057106288048.
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The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP–protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
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Pediaditakis, Peter, Jae-Sung Kim, Lihua He, Xun Zhang, Lee M. Graves, and John J. Lemasters. "Inhibition of the mitochondrial permeability transition by protein kinase A in rat liver mitochondria and hepatocytes." Biochemical Journal 431, no. 3 (October 11, 2010): 411–21. http://dx.doi.org/10.1042/bj20091741.
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NO and cGMP administered at reperfusion after ischaemia prevent injury to hepatocytes mediated by the MPT (mitochondrial permeability transition). To characterize further the mechanism of protection, the ability of hepatic cytosol in combination with cyclic nucleotides to delay onset of the calcium-induced MPT was evaluated in isolated rat liver mitochondria. Liver cytosol plus cGMP or cAMP dose-dependently inhibited the MPT, required ATP hydrolysis for inhibition and did not inhibit mitochondrial calcium uptake. Specific peptide inhibitors for PKA (protein kinase A), but not PKG (protein kinase G), abolished cytosol-induced inhibition of MPT onset. Activity assays showed a cGMP- and cAMP-stimulated protein kinase activity in liver cytosol that was completely inhibited by PKI, a PKA peptide inhibitor. Size-exclusion chromatography of liver cytosol produced a single peak of cGMP/cAMP-stimulated kinase activity with an estimated protein size of 180–220 kDa. This fraction was PKI-sensitive and delayed onset of the MPT. Incubation of active catalytic PKA subunit directly with mitochondria in the absence of cytosol and cyclic nucleotide also delayed MPT onset, and incubation with purified outer membranes led to phosphorylation of a major 31 kDa band. After ischaemia, administration at reperfusion of membrane-permeant cAMPs and cAMP-mobilizing glucagon prevented reperfusion injury to hepatocytes. In conclusion, PKA in liver cytosol activated by cGMP or cAMP acts directly on mitochondria to delay onset of the MPT and protect hepatocytes from cell death after ischaemia/reperfusion.
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Gray, Jonathan J., Philip E. Bickler, Christian S. Fahlman, Xinhua Zhan, and Jennifer A. Schuyler. "Isoflurane Neuroprotection in Hypoxic Hippocampal Slice Cultures Involves Increases in Intracellular Ca2+and Mitogen-activated Protein Kinases." Anesthesiology 102, no. 3 (March 1, 2005): 606–15. http://dx.doi.org/10.1097/00000542-200503000-00020.
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Background The volatile anesthetic isoflurane reduces acute and delayed neuron death in vitro models of brain ischemia, an action that the authors hypothesize is related to moderate increases in intracellular calcium concentration ([Ca2+]i). Specifically, the authors propose that during hypoxia, moderate increases in [Ca2+]i in the presence of isoflurane stimulates the Ca2+-dependent phosphorylation of members of the mitogen-activated protein kinase (MAP) kinase Ras-Raf-MEK-ERK pathway that are critical for neuroprotective signaling and suppression of apoptosis. Methods Death of CA1, CA3, and dentate neurons in rat hippocampal slice cultures was assessed by propidium iodide fluorescence 48-72 h after 60-75 min of hypoxia. [Ca2+]i in CA1 neurons was measured with fura-2 and fura-2 FF. Concentrations of the survival-signaling proteins Ras, MEK, MAP kinase p42/44, and protein kinase B (Akt) were assessed by immunostaining, and specific inhibitors were used to ascertain the role of Ca2+ and MAP kinases in mediating survival. Results Isoflurane, 1%, decreased neuron death in CA1, CA3, and dentate gyrus neurons after 60 but not 75 min of hypoxia. Survival of CA1 neurons required an inositol triphosphate receptor-dependent increase in [Ca2+]i of 30-100 nm that activated the Ras-Raf-MEK-ERK (p44/42) signaling pathway. Isoflurane also increased the phosphorylation of Akt during hypoxia. Conclusions Isoflurane stimulates the phosphorylation of survival signaling proteins in hypoxic neurons. The mechanism involves a moderate increase in [Ca2+]i from release of Ca from inositol triphosphate receptor-dependent intracellular stores. The increase in [Ca2+]i sets in motion signaling via Ras and the MAP kinase p42/44 pathway and the antiapoptotic factor Akt. Isoflurane neuroprotection thus involves intracellular signaling well known to suppress both excitotoxic and apoptotic/delayed cell death.
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Dudek, F. Edward, and Philip A. Williams. "Does Neuroprotection Prevent Epileptogenesis?" Epilepsy Currents 3, no. 2 (March 2003): 68–69. http://dx.doi.org/10.1111/j.1535-7597.2003.03213.x.
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Delayed Sclerosis, Neuroprotection, and Limbic Epileptogenesis After Status Epilepticus in the Rat Ebert U, Brandt C, Loscher W Epilepsia 2002;43(suppl 5):86–95 Purpose Hippocampal sclerosis and massive neurodegeneration in other parts of the limbic system are considered hallmarks of temporal lobe epilepsy. With the rat model of kainate-induced status epilepticus, we sought to determine if limbic sclerosis after an excitotoxic insult follows a delayed type of neurodegeneration and is thus accessible to neuroprotective intervention after the insult. Effective pharmacologic neuroprotection after status epilepticus also addresses the old question of whether degenerative morphologic changes after an epilepsy-inducing event like status epilepticus are the primary cause of epileptogenesis (i.e., the development of recurrent spontaneous seizures) during the following weeks. Methods Female Wistar rats after 90 minutes of generalized status epilepticus were used. Molecular biologic and histologic techniques were used to demonstrate markers of delayed cell death (apoptosis) 48 hours after the status. The neuroprotective effects of i.c.v. injections of caspase inhibitors and systemic injections of the anticonvulsant drugs (AEDs) dizocilpine and retigabine (RGB) after the status epilepticus were studied. The effect of neuroprotective intervention on the development of recurrent spontaneous seizures was investigated by behavioral observation of the rats. Results After generalized status epilepticus in Wistar rats, massive sclerosis of the hippocampus and the piriform cortex occurred. TUNEL labeling and electron microscopy revealed that apoptosis is involved in the degenerative processes. Immunohistochemical analysis of the time course of the expression of the proapoptotic protein Bax suggested a maximal induction of apoptosis 24 to 48 hours after the status. Application of caspase inhibitors before or after the status did not reduce lesions, although Bax labeling was reduced. Injection of dizocilpine and to a lower extent also of RGB after the status prevented limbic neurodegeneration and expression of markers of apoptosis. However, the neuroprotection by dizocilpine did not prevent the development of recurrent spontaneous seizures. Conclusions Prolonged seizure activity can induce delayed sclerosis in the hippocampus and other parts of the limbic system. This delayed cell loss can be prevented by neuroprotective drugs after status epilepticus. However, the damage in limbic brain regions is not the main reason for limbic epileptogenesis and the occurrence of recurrent spontaneous seizures.
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Xu, Fangling, Xiaodong Liang, Robert B. Tesh, and Shu-Yuan Xiao. "Characterization of cell-death pathways in Punta Toro virus-induced hepatocyte injury." Journal of General Virology 89, no. 9 (September 1, 2008): 2175–81. http://dx.doi.org/10.1099/vir.0.2008/001644-0.
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Punta Toro virus (PTV; genus Phlebovirus, family Bunyaviridae) causes apoptosis of hepatocytes in vivo in experimentally infected hamsters and in vitro in cultured HepG2 cells. Screening for expression of apoptosis-related genes has shown alterations in the genes for tumour necrosis factor-α (TNF-α) and the TNF receptor family. This study examined the roles of the TNF receptor-related extrinsic pathway and the Bcl-2 family-associated mitochondrial pathway in PTV-induced cell death. The effects of caspase inhibitors (caspIs) and TNF on cellular viability, virus replication, and morphological and biochemical changes in apoptosis were examined in HepG2 cells at different time points after infection with PTV (Adames strain). The results showed that caspIs dampened the virus-induced reduction in cellular viability, partially suppressed and delayed viral titres and antigen expression, and partially decreased the expression of apoptotic genes, caspase activities and DNA fragmentation. TNF treatment further decreased cellular viability after PTV infection and increased the level of apoptosis, whilst caspIs partially inhibited these effects. These findings indicate that TNF, caspase-8 and caspase-9 contribute to PTV-induced hepatocytic apoptosis and that additional mediators are probably also involved in this process. These mediators from different pathways correlated with one another and may be interlinked.
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Bloomer, Chance H., Andrew T. Faucheux, Alexander M. Quattlebaum, Catherine A. Elko, John Hunting, Lara M. Khoury, Eric Olson, Rebecca Omlor, and Thomas William Lycan. "Palliative care consultation and end-of-life outcomes in a retrospective cohort of patients treated with immune checkpoint inhibitors." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 6577. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.6577.
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6577 Background: Immune checkpoint inhibitors (ICI) can prolong survival for various cancers and are generally available as treatment options for most patients because of their favorable adverse effect profile. Although ICIs provide treatment for many patients who would otherwise be out of options, their variable and often delayed efficacy may postpone the de-escalation of care at the end of life. Palliative Care consultation (PCC) is well-established among patients receiving cytotoxic chemotherapy, but its effectiveness is less certain among patients receiving newer treatment modalities. We aimed to test the association of PCC with end-of-life (EOL) outcomes among patients treated with an ICI for any type of cancer. Methods: We created a retrospective registry of all patients who received at least one dose of ICI for any indication between 2/1/2011 and 4/7/2022 at a comprehensive cancer center and its outreach clinics. The investigators created a secure, cloud-based registry (REDCap), validated it with data quality rules, and resolved all discrepancies; clinical research specialists at Vasta Global captured most of the data. We used the chi-square test to compare categorical variables, defined statistical significance as p < 0.05, and used SAS version 9.4 for analyses. The study had institutional IRB approval. Results: The cohort consisted of 3,142 patients with lung cancer (45%) as the most common cancer type, followed by melanoma (14%) and head and neck squamous cell carcinoma (9%). ICI was most often given in the first line setting (46%) with good baseline performance status (ECOG 0-1, 50%). 915 (29%) patients had PCC, which was associated with a higher rate of code status de-escalation from “Full Code” at any point before death (92% vs. 87%, p 0.007). There was no association between PCC and either the initiation of ICI within 30 days of death (7% vs. 5%, p .0172) or any dose of ICI within 14 days of death (5% vs. 6%, p 0.33). Among patients with a confirmed location of death (1013, 32%), PCC was associated with a similar rate of death in the hospital at any level of care (30% vs. 28%, p 0.51). Conclusions: PCC was associated with code status de-escalation before death but similar risks of late ICI dosing or inpatient status at the time of death. Further studies are needed to risk-stratify patients starting ICI to identify the subgroups that would benefit the most from PCC.
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Atiq, Mohammad Omar, Goutam Chakraborty, Subhiksha Nandakumar, Ying Zhang Mazzu, Konrad H. Stopsack, Yuki Yoshikawa, Gwo-Shu Mary Lee, and Philip W. Kantoff. "Checkpoint kinase inhibition in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 150. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.150.
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150 Background: Poly ADP-ribose polymerase inhibitors (PARPi) have shown promise in the treatment of metastatic castration-resistant prostate cancer patients with DNA damage response defects . The phase 3 PROfound trial showed olaparib delayed the time to radiographic progression or death as compared with abiraterone or enzalutamide. In addition to olaparib, three other PARPi are in Phase 3 trials in prostate cancer (PC): rucaparib, talazoparib, and niraparib. Despite responses, resistance is common and treatment options for PARPi-resistant patients are limited. In this study, we observed de novo activation of checkpoint kinases (CHEK) in talazoparib-resistant (TR) PC cells. Therefore, we hypothesized that targeting CHEK may mitigate resistance to PARPi in PC. Methods: We developed TR human prostate cancer PC3 (low BRCA2 protein due to heterozygous deletion of BRCA2) cells. We performed phosphoproteomic analysis to identify possible mechanisms of talazoparib resistance in PC3 cells and validated the results with Western blot. Results: TR-PC3 cells proliferated slower and had a significant increase in the phosphorylation of CHEK2 compared to parental (p) PC3. Treatment with a CHEK2-selective inhibitor, CCT241533, did not affect cell growth in TR-PC3 cells. Conversely, treatment with a CHEK 1/2 inhibitor, prexasertib, led to significant cell growth inhibition in TR-PC3 at a much lower IG 50% concentration compared to pPC3. RNAi-mediated knockdown validated the superior efficacy of combined CHEK1 and CHEK2 inhibition since this combination produced the greatest cell growth inhibition seen in both TR-PC3 and de novo PARPi-resistant p22RV1. Treatment of pPC-3 and p22RV1 with combinations of talazoparib and prexasertib showed greater cell growth inhibition compared to either drug alone. Conclusions: Resistance to PARPi in PC cells with deletion of BRCA2 may potentially be overcome with CHEK inhibition. Moreover, our preliminary data suggested that the effect of PARPi and CHEK inhibitors on PARPi/CHEK inhibitor-naïve PC cells was greatest when used together, indicating that patients with PC may experience greatest anti-tumor activity of the two drugs when they are used in combination.
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Bancila, M., J. C. Copin, Y. Daali, B. Schatlo, Y. Gasche, and Philippe Bijlenga. "Two structurally different T-type Ca2+ channel inhibitors, mibefradil and pimozide, protect CA1 neurons from delayed death after global ischemia in rats." Fundamental & Clinical Pharmacology 25, no. 4 (October 6, 2010): 469–78. http://dx.doi.org/10.1111/j.1472-8206.2010.00879.x.
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Craig, Amanda J., Bruno P. Meloni, Paul Watt, and Neville W. Knuckey. "Attenuation of Neuronal Death by Peptide Inhibitors of AP-1 Activation in Acute and Delayed In Vitro Ischaemia (Oxygen/Glucose Deprivation) Models." International Journal of Peptide Research and Therapeutics 17, no. 1 (November 4, 2010): 1–6. http://dx.doi.org/10.1007/s10989-010-9234-8.
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Martin, S. J., S. V. Lennon, A. M. Bonham, and T. G. Cotter. "Induction of apoptosis (programmed cell death) in human leukemic HL-60 cells by inhibition of RNA or protein synthesis." Journal of Immunology 145, no. 6 (September 15, 1990): 1859–67. http://dx.doi.org/10.4049/jimmunol.145.6.1859.
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Abstract Apoptosis is regarded as a suicidal cell response since the dying cell appears to be an active participant. Previous studies have shown that apoptosis of various murine cell types, induced by a variety of stimuli, required RNA and/or protein synthesis. However, when human promyelocytic leukemia HL-60 cells were induced to undergo apoptosis by treatment with the calcium ionophore A23187 or microtubule-disrupting agents, in the presence of inhibitors of macromolecular synthesis, apoptosis of these cells was neither abrogated nor delayed. Furthermore, the presence of either cycloheximide, an inhibitor of protein synthesis, or actinomycin D, an RNA synthesis inhibitor, alone was found to induce large scale apoptosis of these cells. Apoptosis in these cells was characterized by cell and chromatin condensation followed by nuclear and DNA fragmentation. In common with many other studies, this DNA fragmentation was found to have an approximately 200-bp multiple pattern, which is consistent with the activation of an endogenous endonuclease which cleaves at internucleosomal sites. Calcium-dependent endonuclease activity of this type was also detected in the isolated nuclei of untreated HL-60 cells. The morphologic and biochemical changes characteristic of apoptosis were found to precede cell death, as measured by trypan blue uptake and were completely distinct from death caused by toxic stimuli such as azide, ethanol, or heat treatment. Similar experiments with six other human cell lines confirmed that this phenomenon was not peculiar to the HL-60 cell line. These results suggest that certain dividing cell populations do not require RNA or protein synthesis to undergo apoptosis and further, that continuous transcription and translation of some regulatory protein(s) may be required to maintain control over the apoptotic "machinery" of such cells.
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De Smedt, Eva, Julie Devin, Catharina Muylaert, Nicolas Robert, Guilhem Requirand, Philip Vlummens, Laure Vincent, et al. "G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor–mediated cell death." Blood Advances 5, no. 9 (May 3, 2021): 2325–38. http://dx.doi.org/10.1182/bloodadvances.2020003217.
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Abstract Multiple myeloma (MM) is an (epi)genetic highly heterogeneous plasma cell malignancy that remains mostly incurable. Deregulated expression and/or genetic defects in epigenetic-modifying enzymes contribute to high-risk disease and MM progression. Overexpression of the histone methyltransferase G9a was reported in several cancers, including MM, correlating with disease progression, metastasis, and poor prognosis. However, the exact role of G9a and its interaction partner G9a-like protein (GLP) in MM biology and the underlying mechanisms of action remain poorly understood. Here, we report that high G9a RNA levels are associated with a worse disease outcome in newly diagnosed and relapsed MM patients. G9a/GLP targeting using the specific G9a/GLP inhibitors BIX01294 and UNC0638 induces a G1-phase arrest and apoptosis in MM cell lines and reduces primary MM cell viability. Mechanistic studies revealed that G9a/GLP targeting promotes autophagy-associated apoptosis by inactivating the mTOR/4EBP1 pathway and reducing c-MYC levels. Moreover, genes deregulated by G9a/GLP targeting are associated with repressive histone marks. G9a/GLP targeting sensitizes MM cells to the proteasome inhibitors (PIs) bortezomib and carfilzomib, by (further) reducing mTOR signaling and c-MYC levels and activating p-38 and SAPK/JNK signaling. Therapeutic treatment of 5TGM1 mice with BIX01294 delayed in vivo MM tumor growth, and cotreatment with bortezomib resulted in a further reduction in tumor burden and a significantly prolonged survival. In conclusion, we provide evidence that the histone methyltransferases G9a/GLP support MM cell growth and survival by blocking basal autophagy and sustaining high c-MYC levels. G9a/GLP targeting represents a promising strategy to improve PI-based treatment in patients with high G9a/GLP levels.
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Cheng, Hongwei, Ian Charles, Andrew F. James, Ana P. Abdala, and Jules C. Hancox. "Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome." International Journal of Molecular Sciences 23, no. 10 (May 20, 2022): 5735. http://dx.doi.org/10.3390/ijms23105735.
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Rett syndrome (RTT) is a severe developmental disorder that is strongly linked to mutations in the MECP2 gene. RTT has been associated with sudden unexplained death and ECG QT interval prolongation. There are mixed reports regarding QT prolongation in mouse models of RTT, with some evidence that loss of Mecp2 function enhances cardiac late Na current, INa,Late. The present study was undertaken in order to investigate both ECG and ventricular AP characteristics in the Mecp2Null/Y male murine RTT model and to interrogate both fast INa and INa,Late in myocytes from the model. ECG recordings from 8–10-week-old Mecp2Null/Y male mice revealed prolongation of the QT and rate corrected QT (QTc) intervals and QRS widening compared to wild-type (WT) controls. Action potentials (APs) from Mecp2Null/Y myocytes exhibited longer APD75 and APD90 values, increased triangulation and instability. INa,Late was also significantly larger in Mecp2Null/Y than WT myocytes and was insensitive to the Nav1.8 inhibitor A-803467. Selective recordings of fast INa revealed a decrease in peak current amplitude without significant voltage shifts in activation or inactivation V0.5. Fast INa ‘window current’ was reduced in RTT myocytes; small but significant alterations of inactivation and reactivation time-courses were detected. Effects of two INa,Late inhibitors, ranolazine and GS-6615 (eleclazine), were investigated. Treatment with 30 µM ranolazine produced similar levels of inhibition of INa,Late in WT and Mecp2Null/Y myocytes, but produced ventricular AP prolongation not abbreviation. In contrast, 10 µM GS-6615 both inhibited INa,Late and shortened ventricular AP duration. The observed changes in INa and INa,Late can account for the corresponding ECG changes in this RTT model. GS-6615 merits further investigation as a potential treatment for QT prolongation in RTT.
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Gonugunta, Amrit S., Mitchell S. von Itzstein, Hong Mu-Mosley, Farjana Fattah, J. David Farrar, Angela Mobely, Sawsan Rashdan, et al. "Humoral and cellular correlates of a novel immune-related adverse event and its treatment." Journal for ImmunoTherapy of Cancer 9, no. 12 (December 2021): e003585. http://dx.doi.org/10.1136/jitc-2021-003585.
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Immune-related adverse events (irAE) may affect almost any organ system and occur at any point during treatment with immune checkpoint inhibitors (ICI). We present a patient with advanced lung cancer receiving antiprogrammed death 1 checkpoint inhibitor who developed a delayed-onset visual irAE treated with corticosteroids. Through assessment of longitudinal biospecimens, we analyzed serial autoantibodies, cytokines, and cellular populations. Months after ICI initiation and preceding clinical toxicity, the patient developed broad increases in cytokines (most notably interleukin-6 (IL-6), interferon-γ (IFNγ), C-X-C motif chemokine ligand 2 (CXCL2), and C–C motif chemokine ligand 17 (CCL17)), autoantibodies (including anti-angiotensin receptor, α-actin, and amyloid), CD8 T cells, and plasmablasts. Such changes were not observed in healthy controls and ICI-treated patients without irAE. Administration of corticosteroids resulted in immediate and profound decreases in cytokines, autoantibodies, and inflammatory cells. This case highlights the potential for late-onset changes in humoral and cellular immunity in patients receiving ICI. It also demonstrates the biologic effects of corticosteroids on these parameters. Application of humoral and cellular immune biomarkers across ICI populations may inform toxicity monitoring and management.